Osteoporosis is a complex disease of decreased bone mass that impacts half of all Americans over the age of 50 and results in debilitating bone fracture. Clinically, bone mineral density (BMD) is used for assessing fracture risk, but BMD is an imperfect predictor of fracture incidence. The strength of a whole bone is dictated by the amount of bone present, its geometry and internal architecture, and the mechanical integrity of its structural material. Numerous studies have established that many phenotypic traits associated with bone strength are controlled genetically, but most of these studies did not consider the composition of the bone matrix. Teriparatide is a recombinant form of the first 34 amino acids of parathyroid hormone (PTH) and is a clinically established anabolic therapy for bone. Using the criterion of a 3% change in BMD as evidence of response to Teriparatide, studies have shown that up to 9% of patients do not show an increase in BMD after 18 months of treatment. However, 77% of these non-responsive patients did show a robust increase in bone formation markers. It has been suggested that this diversity in response may be due to genetic factors. The overall goal of this project is to identify genes that participate in the regulation of bone mechanical integrity, and which do so via interaction with parathyroid hormone (PTH). In this application we will be using the Diversity Outbred (DO), which was designed for genetic studies to overcome issues of mapping resolution and phenotypic diversity. In a pilot study using the DO, we showed that we can identify candidate genes, rather than just regions within the genome, that are associated with bone size and architecture. In the first Aim, we will expand our phenotyping to include tests of mechanical integrity at the tissue level, mapping high-resolution quantitative trait loci (QTL) for a collection of complementary traits ranging in length scale from whole body skeletal mass to individual bone strength, architecture, and size, to tissue-level mechanical integrity. As part of this aim, we seek identify genes that interact with intermittent treatment with PTH:1-34 to impact bone. In the second Aim, we will use the 8 founder strains of the DO to study the impact of PTH on bone composition and how that impacts bone strength. We will conduct gene expression studies to build gene-gene interaction networks to identify mechanisms by which PTH impacts bone. Our comprehensive phenotyping pipeline will allow us to identify multiple new genes instrumental for controlling bone mechanical integrity, and that by incorporating PTH:1-34 treatment into study design we will additionally identify key genes controlling bone that genetically are ?context specific? in that their genetic differences are only unmasked when environment is altered. These genes will help us to understand how PTH impacts bone in aspects not previously known.